Smoking and alcohol consumption are each major risk factors for cardiovascular morbidity and mortality. Cardiovascular and all-cause morbidity and mortality from tobacco are especially high in Eastern Europe, where tobacco-related death rates are still increasing. Alcohol consumption is also linked to increased prevalence of cardiovascular disease in Eastern Europe. The sudden cardiac death mortality rates in Polish men aged 35-64 increased 6-fold during the last 30 years. This may be attributed to the high and increasing prevalence of smoking and alcohol abuse in Poland. While both smoking and alcohol have been implicated in chronic cardiac and vascular disease, compelling epidemiologic observations appear to link both smoking and alcohol to acute cardiovascular events such as stroke, myocardial infarction and sudden death. Importantly, cardiovascular risk appears to be especially increased by the combined use of cigarettes and alcohol. The underlying mechanism relating smoking and alcohol consumption to acute cardiovascular events is not clear. One potential candidate is the sympathetic nervous system. Sympathetic activation in response to smoking plus alcohol may be potentiated in patients with hypertension and heart failure, in whom baroreflex sensitivity is known to be impaired. Sympathetic activation might be an important triggering mechanism translating vascular disease into an acute cardiovascular event. We propose a series of studies directed at understanding the mechanisms underlying the cardiovascular responses to cigarette smoking during alcohol consumption, in healthy humans and in patients with cardiovascular disease. We will test the following specific hypotheses. 1) Smoking and alcohol have synergistic effects on sympathetic neural outflow, heart rate and blood pressure in normal humans. 2) The sympathetic, pressor and tachycardic responses to cigarette smoking combined with alcohol are potentiated in patients with hypertension and heart failure. Exciting preliminary data provide strong support for the hypotheses to be tested. This proposal builds on our broad experience in studies of cigarette smoke, alcohol and neurohumoral circulatory control, and should contribute significantly to our understanding of the mechanisms linking cigarette smoking and alcohol to acute cardiovascular events.